This project will evaluate the putative role of hepatic sinusoidal endothelial xanthine oxidase as an inflammatory signal transduction mechanism, transducing circulating proinflammatory signals (TNFalpha, gammaINF, endotoxin [LPS]) by virtue of oxidant generation causing the upregulation of endothelial surface adhesion molecules, and the consequent arrest, trapping and activation of circulating neutrophils, a mechanism to effect phagocytic killing of microorganisms, an essential component of reticuloendothelial system function. Specifically, this project will study this in the intact organism, in real time using a combination of intravital microscopy of the rat liver in vivo, intravital microscopy of the isolated perfused rat liver ex vivo, and histologic and histochemical evaluation of livers taken from intact living rats treated in vivo. This project will focus on identifying the response to the above proinflammatory agonists, the identification of the adhesion molecules expressed, establishment of the role of xanthine oxidase-generated oxidants and the role of intercellular calcium fluxes in triggering this response. Studies will be conducted in the laboratories of Drs. Gregory Bulkley, Mark Clemens and marshall Montrose. When combined with a focused program of course work, this two year fellowship should thereby provide sound fundamental background for a subsequent career in academic general surgery, following the completion of clinical training.